Nucleic acids play important role in many biological functions, particularly in genetic information storage, gene expression and protein synthesis [Watson, J. D. & Crick, F. H. (1953) Nature 171, 737-8; Storz, G. (2002) Science 296, 1260-1263]. DNA is hydrolytically more stable than RNA due to the absence of the 2′-OH. The other major chemical difference between DNA and RNA is the presence of the 5-methyl group in DNA thymine comparing to RNA uracil. Since both thymine (5-methyl uracil) and uracil can form the same type of base pair with adenine (T-A and U-A pairs), it is essential to understand the fundamental functions of the C5 methyl group on thymine. Interestingly, the C5-methylated uracil (thymine) is also observed in many natural RNAs, such as ribosomal RNAs and tRNAs [Becker, H. F., Motorin, Y., Florentz, C., Giege, R. & Grosjean, H. (1998) Nucleic Acids Res 26, 3991-7; Sprinzl, M. & Vassilenko, K. S. (2005) Nucleic Acids Res 33, D139-40; McCloskey, J. A. & Rozenski, J. (2005) Nucleic Acids Res 33, D135-8]. In addition, comparing with uracil in RNA, thymine in DNA contributes to better stacking interaction [Wang, S. & Kool, E. T. (1995) Biochemistry 34, 4125-32] in part by providing CH3. . . π interaction with a 5′-preceding purine or pyrimidine moiety [Umezawa, Y. & Nishio, M. (2002) Nucleic Acids Res 30, 2183-92; Chatterjee, S., Pathmasiri, W. & Chattopadhyaya, J. (2005) Org Biomol Chem 3, 3911-5]. Furthermore, methylated cytosine at the C5 and N4 as well as methylated adenine at the NO in DNA form epigenetic marks and allow modulation of DNA-protein interactions [Suzuki, M. M. & Bird, A. (2008) Nat Rev Genet 9, 465-76; Ng, L. J., Cropley, J. E., Pickett, H. A., Reddel, R. R. & Suter, C. M. (2009) Nucleic Acids Res; Petrovich, M. & Veprintsev, D. B. (2009) J Mol Biol 386, 72-80; Manlius, M. G. & Casadesus, J. (2009) FEMS Microbiol Rev], which gives methylated DNA biological advantages in regulation, replication, transcription, and nuclease resistance [Low, D. A. & Casadesus, J. (2008) Curr Opin Microbiol 11, 106-12]. From the RNA molecular evolution point of view [Gesteland, R. F. C., T. R.; Atkins, J. F., Eds. (2006) The RNA World: The Nature of Modern RNA Suggests a Prebiotic RNA, ed. 3, (Cold Spring Harbor Laboratory Press Cold Spring Harbor, N.Y.)], therefore, the 5-methyl group of thymine in DNA, compared with 5-hydrogen of uracil in RNA, may be considered as the constant DNA methylation.
Interestingly, structure studies of DNA duplexes and DNA-protein complexes indicate a largely varied distance (from 7.4 to 3.4 Å) between the 5-methyl group of a thymine in DNA and the closest non-bridging oxygen (pro-Sp oxygen) of its 5′-phosphate moiety (15-24), suggesting a possible dynamic interaction between this constant methyl group and the phosphate backbone under certain circumstances. This interaction (the hydrogen bonding between the methyl and phosphate groups) might facilitate the duplex unwinding and double strand separation, since DNA duplex conformational changes are involved in many biological processes, such as DNA polymerization, DNA replication and transcription regulations.
Recently atoms with weak electron-negativity (e.g. Carbon) have gained more importance and acceptance as hydrogen-bond donors (such as C—H), although atoms with strong electron-negativity (e.g. oxygen and nitrogen) are traditionally considered in hydrogen bonding as hydrogen-bond donors (such as O—H and N—H). The interactions between donor C—H and hydrogen-bond acceptors (electron donors) [Singh, S. K., Babu, M. M. & Balaram, P. (2003) Proteins 51, 167-71; Uldry, A. C., Griffin, J. M., Yates, J. R., Perez-Torralba, M., Maria, M. D., Webber, A. L., Beaumont, M. L., Samoson, A., Claramunt, R. M., Pickard, C. J. & Brown, S. P. (2008) J Am Chem Soc 130, 945-54; Scheiner, S., Kar, T. & Gu, Y. (2001) J Biol Chem 276, 9832-7; Anbarasu, A., Anand, S. & Sethumadhavan, R. (2007) Biosystems 90, 792-801], such as C—H. . . O═C hydrogen bond in proteins [Singh, S. K., Babu, M. M. & Balaram, P. (2003) Proteins 51, 167-71], C—H. . . O═C in uracil crystal [Uldry, A. C., Griffin, J. M., Yates, J. R., Perez-Torralba, M., Maria, M. D., Webber, A. L., Beaumont, M. L., Samoson, A., Claramunt, R. M., Pickard, C. J. & Brown, S. P. (2008) J Am Chem Soc 130, 945-54] and C—H. . . Cl in a guest-host system [Li, Y. & Flood, A. H. (2008) Angew Chem Int Ed Engl 47, 2649-52], and other non-conventional interactions (such as H. . . πC interaction in RNA) [Sarkhel, S., Rich, A. & Egli, M. (2003) J Am Chem Soc 125, 8998-9] have played critical roles in molecular recognition, catalysis, and DNA duplex stability within chemical and biological systems [Wang, S. & Kool, E. T. (1995) Biochemistry 34, 4125-32; Gesteland, R. F. C., T. R.; Atkins, J. F., Eds. (2006) The RNA World: The Nature of Modern RNA Suggests a Prebiotic RNA, ed. 3, (Cold Spring Harbor Laboratory Press Cold Spring Harbor, N.Y.); Singh, S. K., Babu, M. M. & Balaram, P. (2003) Proteins 51, 167-71; Uldry, A. C., Griffin, J. M., Yates, J. K, Perez-Torralba, M., Maria, M. D., Webber, A. L., Beaumont, M. L., Samoson, A., Claramunt, R. M., Pickard, C. J. & Brown, S. P. (2008) J Am Chem Soc 130, 945-54; Scheiner, S., Kar, T. & Gu, Y. (2001) J Biol Chem 276, 9832-7; Anbarasu, A., Anand, S. & Sethumadhavan, R. (2007) Biosystems 90, 792-801; Li, Y. & Flood, A. H. (2008) Angew Chem Int Ed Engl 47, 2649-52; Sarkhel, S., Rich, A. & Egli, M. (2003) J Am Chem Soc 125, 8998-9; Tewari, A. K. & Dubey, R. (2008) Bioorg Med Chem 16, 126-43]. In addition, the 5-CH3 group of thymidine in DNA can stack on a 5′-proceeding purine or pyrimidine via a CH2—H. . . π (or CH3. . . π) interaction [Umezawa, Y. & Nishio, M. (2002) Nucleic Acids Res 30, 2183-92; Chatterjee, S., Pathmasiri, W. & Chattopadhyaya, J. (2005) Org Biomol Chem 3, 3911-5], where the nucleobase functions as a weak hydrogen-bond acceptor, thereby further contributing to the duplex stability.
Tellurium is a non-metal element with a much larger atomic size (atomic radius: 1.40 Å) [L. Moroder, J. Pept. Sci. 2005, 11, 187-214] in the same elemental family of oxygen (0.73 Å), sulfur (1.02 Å) and selenium (1.16 Å) [J. Sheng, Z. Huang, Int. J. Mol. Sci. 2008, 9, 258-271], and has higher metallic property and stronger electron delocalizability. An electron-rich tellurium atom will likely donate electron and facilitate electron delocalization when it is introduced into DNA duplexes via nucleobases, which are relatively electron-deficient.
The nucleobases play the most critical roles in duplex recognition of nucleic acids. Well-behaved base-pair recognition and sequence-dependent specificity of DNAs and RNAs have stimulated extensive research investigations, such as DNA nano-structure construction and self-assembling [a) J: Zheng, J. J. Birktoft, Y. Chen, T. Wang, R. Sha, P. E. Constantinou, S. L. Ginell, C. Mao, N. C. Seeman, Nature 2009, 461, 74-77. b) E. S. Andersen, M. Dong, M. M. Nielsen, K. Jahn, R. Subramani, W. Mamdouh, M. M. Golas, B. Sander, H. Stark, C. L. Oliveira, J. S. Pedersen, V. Birkedal, F. Besenbacher, K. V. Gothelf, J. Kjems, Nature 2009, 459, 73-76. c) P. W. Rothemund, Nature 2006, 440, 297-302. d) X. Xue, F. Wang, X. Liu, J. Am. Chem. Soc. 2008, 130, 3244-3245], disease and pathogen detection at single molecule level [A. Singer, M. Wanunu, W. Morrison, H. Kuhn, M. Frank-Kamenetskii, A. Meller, Nano. Lett. 2010, 10, 738-742], oligonucleotide drug discovery [K. Tiemann, J. J. Rossi, EMBO Mot. Med. 2009, 1, 142-151], and nanoelectronic device design based on DNA conductivity and charge migration [a) Y. C. Huang, D. Sen, J. Am. Chem. Soc. 2010, 132, 2663-2671. b) I. Kratochvilova, K. Kral, M. Buncek, A. Viskova, S. Nespurek, A. Kochalska, T. Todorciuc, M. Weiter, B. Schneider, Biophys. Chem. 2008, 138, 3-10. c) T. Ito, S. E. Rokita, Angew. Chem. Int. Ed. 2004, 43, 1839-1842. d) R. N. Barnett, C. L. Cleveland, A. Joy, U. Landman, G. B. Schuster, Science 2001, 294, 567-571. e) D. Porath, A. Bezryadin, S. de Vries, C. Dekker, Nature 2000, 403, 635-638. f) H. W. Fink, C. Schonenberger, Nature 1999, 398, 407-410]. Moreover, chemical modifications of nucleobases have been widely used to selectively tailor the biochemical and biophysical properties of DNAs and RNAs and to probe their biochemical and biological mechanisms, including base-pairing specificity, polymerase recognition, and DNA damaging and repairing [a) Z. Yang, F. Chen, S. G. Chamberlin, S. A. Benner, Angew. Chem. Int. Ed. 2010, 49, 177-180. b) M. Egli, P. S. Pallan, Chem. Biodivers. 2010, 7, 60-89. c) A. E. Hassan, J. Sheng, W. Zhang, Z. Huang, J. Am. Chem. Soc. 2010, 132, 2120-2121. d) J. C. Delaney, J. Gao, H. Liu, N. Shrivastav, J. M. Essigmann, E. T. Kool, Angew. Chem. Int. Ed. Engl. 2009, 48, 4524-4527. e) M. Ljungman, Chem. Rev. 2009, 109, 2929-2950.1) A. M. Sismour, S. A. Benner, Nucleic Acids Res. 2005, 33, 5640-5646. g) T. W. Kim, J. C. Delaney, J. M. Essigmann, E. T. Kool, Proc. Natl. Acad. Sci. USA 2005, 102, 15803-15808]. Furthermore, the conductivity of DNAs has been studied extensively via nucleobase modification, metallization and conjugating with conductive nanoparticles or polymers through scanning tunneling microscopy (STM) imaging [I. Kratochvilova, I C Kral, M. Buncek, A. Viskova, S. Nespurek, A. Kochalska, T. Todorciuc, M. Weiter, B. Schneider, Biophys. Chem. 2008, 138.3-10; a) E. Braun, Y. Eichen, U. Sivan, G. Ben-Yoseph, Nature 1998, 391, 775-778. b) J. L. Coffer, S. R. Bigham, X. Li, R. F. Pinizzotto, Y. G. Rho, R. M. Pirtle, I. L. Pirtle, Appl. Phys. Lett. 1996, 69, 3851-3853. c) Y. F. Ma, J. M. Zhang, G. J. Zhang, H. X. He, J. Am. Chem. Soc. 2004, 126, 7097-7101. d) X. Guo, A. A. Gorodetsky, J. Hone, J. K. Barton, C. Nuckolls, Nat. Nanotechnol. 2008, 3, 163-167. e) B. Elias, F. Shao, J. K. Barton, J. Am. Chem. Soc. 2008, 130, 1152-1153].
Therefore, there is a need existing for the identification of new exo-5 position and/or 2-position modifications on the nucleobases of thymidine, ribothymidine, uridine, 2′-deoxyuridine, cytidine, 2′-deoxycytidine, and their derivatives in DNAs, RNAs and modified nucleic acids.